Abstract 927: Tumor-initiating stem cells utilize the immunomodulatory ligand CD80 to promote Treg expansion and cancer relapse

Abstract Although immunotherapy has been a key innovation in cancer treatment, tumor relapse still poses a major challenge for many patients. Recent research has shown that cancer relapse can be caused by a special group of cancer cells enriched with stemness signatures that survive treatments and repopulate tumors. These cells are referred to as tumor-initiating stem cells (tSCs). The mechanisms by which tSCs survive immunotherapy to drive cancer relapse are still unclear. Using a spontaneous squamous cell carcinoma (SCC) mouse model, we found that tSCs have elevated expression of CD80, a surface molecule that provides co-stimulation to T cells. Notably, the loss of CD80 expression on SCC cells led to diminished tumor growth by blunting the expansion of intratumoral regulatory T cells (Tregs). This interaction between epithelial stem cell and Treg cells can also be found during wound repair where CD80 expression by hair follicle stem cells promotes expansion of Tregs in the wound bed. Interestingly, we found that CD80 on epithelial stem cells facilitates Treg expansion by an unconventional mechanism in which the Foxp3 can be directly induced in preactivated tumor infiltrating CD4+ T cells. Collectively, this study reveals a unique mechanism by which tSCs may sculpt an immunosuppressive niche to evade killing and facilitate tumor relapse. Citation Format: Jennifer L. Good, Weijie Guo, Jingyun Luan, Benjamin T. Nicholson, Yuxuan Miao. Tumor-initiating stem cells utilize the immunomodulatory ligand CD80 to promote Treg expansion and cancer relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 927.